Quinuclidine derivatives as muscarinic m3 receptor antagonists

Abstract

The invention provides named compounds of formula (I), pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions and their use in therapy.

1 . A compound selected from the group consisting of:
 (R)-1-[(6-Methyl-pyridin-3-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(6-Methyl-pyrazin-2-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-[(6-trifluoromethyl-pyridazin-3-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-(Benzo[d]isoxazol-3-ylcarbamoylmethyl)-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-(Pyridazin-3-ylcarbamoylmethyl)-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(5-Methyl-isoxazol-3-ylcarbamoyl)-methyl]-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(3-Methyl-isoxazol-5-ylcarbamoyl)-methyl]-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(3-Fluoro-phenylcarbamoyl)-methyl]-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(5-Methyl-pyrazin-2-ylcarbamoyl)-methyl]-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-(Benzo[d]isoxazol-3-ylcarbamoylmethyl)-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-(Pyrazin-2-ylcarbamoylmethyl)-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-[1-(3-Fluoro-phenyl)-cycloheptanecarbonyloxy]-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-[1-(3-Fluoro-phenyl)-cycloheptanecarbonyloxy]-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(pyridin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(pyridin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(5-Fluoro-pyridin-2-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(5-Methyl-pyridin-2-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(pyridin-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(2-Methyl-pyridin-4-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-Phenylcarbamoylmethyl-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(2-Fluoro-phenylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(2,3-Difluoro-phenylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[2-(4-Fluoro-phenoxy)-ethyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-phenyl-cycloheptanecarbonyloxy)-1-(pyridazin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(5-Fluoro-pyridin-3-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-phenyl-cycloheptanecarbonyloxy)-1-[2-(pyridin-3-yloxy)-ethyl]-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(6-Methyl-pyridin-2-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(o-tolylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(2-pyrazin-2-yl-ethyl)-1-azonia-bicyclo[2.2.2]octane X;   (S)-1-(3-Phenoxy-propyl)-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-{[2-(3-Fluoro-phenoxy)-ethylcarbamoyl]-methyl}-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(3,5-Difluoro-phenylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[2-(4-methoxy-benzyloxy)-ethyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-(2-Phenethyloxy-ethyl)-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(2,6-Difluoro-phenylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(Methyl-phenyl-carbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[3-(4-Cyano-phenoxy)-propyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(2,5-Difluoro-phenylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[2-(4-Cyano-benzyloxy)-ethyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-[(6-trifluoromethyl-pyridin-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(4-Methyl-pyridin-2-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(p-tolylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(m-tolylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-(Oxazol-2-ylcarbamoylmethyl)-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(6-Methyl-pyridazin-3-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(pyrimidin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(5-Cyano-pyridin-2-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(pyrimidin-5-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(3-Fluoro-pyridin-2-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(3-Fluoro-pyridin-4-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-{2-[(pyrazine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-([1,2,4]thiadiazol-5-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-{3-[(pyridine-2-carbonyl)-amino]-propyl}-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(2-Methyl-pyrimidin-4-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-1-[(6-Methyl-pyrimidin-4-ylcarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azonia-bicyclo[2.2.2]octane X;   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-{2-[(pyridine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane X; and   (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(3-pyridin-4-yl-propyl)-1-azonia-bicyclo[2.2.2]octane X;   wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.   
     
     
         2 . A compound according to  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein X represents a pharmaceutically acceptable anion of a mono or polyvalent acid. 
       
     
     
         3 . A pharmaceutical composition comprising a compound according to  claim 1 , in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         4 . A process for the preparation of a pharmaceutical composition as claimed in  claim 3 , which comprises mixing a compound of according to  claim 1  or  claim 2  with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . A method of treating chronic obstructive pulmonary disease in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound according to  claim 1 . 
     
     
         8 . A pharmaceutical product comprising, in combination, a first active ingredient which is a compound according to  claim 1 , and at least one further active ingredient selected from:
 a phosphodiesterase inhibitor,   a β2 adrenoceptor agonist,   a modulator of chemokine receptor function,   an inhibitor of kinase function,   a protease inhibitor,   a steroidal glucocorticoid receptor agonist, and a   a non-steroidal glucocorticoid receptor agonist.